Receptor Tyrosine Kinase (RTK) inhibitors, such as erlotinib/tarceva, have been introduced
in the past decade as a promising therapeutic option in Head and Neck Squamous Cell
Carcinoma (HNSCC), however, they lack significant efficacy as single agents. As a result,
RTK inhibitors require a combination based therapeutic approach with other treatment
modalities. To uncover such a combination of agents, we performed a high throughput
Prestwick library screen that included 1200 compounds approved by the FDA on HNSCC
cell lines and found that monensin, a coccidial antibiotic, synergistically enhanced the
cytotoxicity of erlotinib. RT-PCR revealed that monensin induced the expression of
Activation of Transcription Factor (ATF) 3 and its downstream target C/EBP homologous
protein (CHOP) which are key regulators of apoptosis. Furthermore, RNA-Seq analysis
suggests that monensin augments erlotinib cytotoxicity by disturbing lipid and sterol
biosynthesis. Therefore, identifying the mechanism of action exerted by monensin may open alternative avenues of cancer treatment.
| Identifer | oai:union.ndltd.org:uottawa.ca/oai:ruor.uottawa.ca:10393/24405 |
| Date | January 2013 |
| Creators | Khalil, Dayekh |
| Contributors | Dimitroulakos, Jim |
| Publisher | Université d'Ottawa / University of Ottawa |
| Source Sets | Université d’Ottawa |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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